Four investigators with long standing interest in ion channels and synaptic biology have come together to study effects of acetylcholine (ACh) on the activation and modulation of ion channels in the central nervous system. Changes in the effective concentration of ACh or in the number of ACh receptors (AChRs) have been associated with cognitive disorders, attention deficits, memory loss in normal subjects and in Alzheimer's patients, in Parkinson's Disease and in drug seeking behaviors. Work described in this Program Project includes analyses of nicotinic and muscarinic mechanisms that may shed light on these disorders. The Program developed naturally out of collaborative projects already begun by the four investigators. Together, we plan to investigate the regulation of nicotinic AChRs by neuregulins, a family of trophic factors expressed in the brain; the role of nicotinic and muscarinic receptors in modulating synaptic transmission; the modulation by ACh of several types of voltage gated ion channels; the distribution and role of G-protein coupled potassium channels (GIRKs) in regulating neuronal firing. Several different regions of the brain will be studied including the hippocampus, substantia nigra, ventral tegmental area, globus pallidus, medial habenula, interpeduncular nucleus, and cerebellum. Several preparations will be employed including freshly dissociated neurons, nerve cell cultures, brain slices and genetically altered mice. The primary tools are electrophysiological as we are primarily concerned with ACh induced changes in synaptic function and neuronal firing patterns. The projects are closely related and interactions have already emerged that greatly facilitate progress in each area. These interactions will broaden the scope of our work in the future.